OUTRIDER: A Statistical Method for Detecting Aberrantly Expressed Genes in RNA Sequencing Data.

Abstract:

:RNA sequencing (RNA-seq) is gaining popularity as a complementary assay to genome sequencing for precisely identifying the molecular causes of rare disorders. A powerful approach is to identify aberrant gene expression levels as potential pathogenic events. However, existing methods for detecting aberrant read counts in RNA-seq data either lack assessments of statistical significance, so that establishing cutoffs is arbitrary, or rely on subjective manual corrections for confounders. Here, we describe OUTRIDER (Outlier in RNA-Seq Finder), an algorithm developed to address these issues. The algorithm uses an autoencoder to model read-count expectations according to the gene covariation resulting from technical, environmental, or common genetic variations. Given these expectations, the RNA-seq read counts are assumed to follow a negative binomial distribution with a gene-specific dispersion. Outliers are then identified as read counts that significantly deviate from this distribution. The model is automatically fitted to achieve the best recall of artificially corrupted data. Precision-recall analyses using simulated outlier read counts demonstrated the importance of controlling for covariation and significance-based thresholds. OUTRIDER is open source and includes functions for filtering out genes not expressed in a dataset, for identifying outlier samples with too many aberrantly expressed genes, and for detecting aberrant gene expression on the basis of false-discovery-rate-adjusted p values. Overall, OUTRIDER provides an end-to-end solution for identifying aberrantly expressed genes and is suitable for use by rare-disease diagnostic platforms.

journal_name

Am J Hum Genet

authors

Brechtmann F,Mertes C,Matusevičiūtė A,Yépez VA,Avsec Ž,Herzog M,Bader DM,Prokisch H,Gagneur J

doi

10.1016/j.ajhg.2018.10.025

subject

Has Abstract

pub_date

2018-12-06 00:00:00

pages

907-917

issue

6

eissn

0002-9297

issn

1537-6605

pii

S0002-9297(18)30401-4

journal_volume

103

pub_type

杂志文章
  • Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V.

    abstract::Charcot-Marie-Tooth disease type 2D (CMT2D) and distal spinal muscular atrophy type V (dSMA-V) are axonal peripheral neuropathies inherited in an autosomal dominant fashion. Our previous genetic and physical mapping efforts localized the responsible gene(s) to a well-defined region on human chromosome 7p. Here, we rep...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/375039

    authors: Antonellis A,Ellsworth RE,Sambuughin N,Puls I,Abel A,Lee-Lin SQ,Jordanova A,Kremensky I,Christodoulou K,Middleton LT,Sivakumar K,Ionasescu V,Funalot B,Vance JM,Goldfarb LG,Fischbeck KH,Green ED

    更新日期:2003-05-01 00:00:00

  • Optimal sampling for pedigree analysis: relatives of affected probands.

    abstract::Criteria and rules are derived for the most statistically efficient sampling of relatives of affected probands under a simple class of standard genetic models. Results show that the optimal relative type depends on the alternative hypotheses of particular interest. Thus, there is no uniformly optimal strategy, but the...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Thompson EA

    更新日期:1981-11-01 00:00:00

  • Mutations in ROGDI Cause Kohlschütter-Tönz Syndrome.

    abstract::Kohlschütter-Tönz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regression, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping an...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2012.02.012

    authors: Schossig A,Wolf NI,Fischer C,Fischer M,Stocker G,Pabinger S,Dander A,Steiner B,Tönz O,Kotzot D,Haberlandt E,Amberger A,Burwinkel B,Wimmer K,Fauth C,Grond-Ginsbach C,Koch MJ,Deichmann A,von Kalle C,Bartram CR,Kohls

    更新日期:2012-04-06 00:00:00

  • Cigarette smoking and Down syndrome.

    abstract::A matched case-control study of 100 mothers of Down syndrome children, 100 mothers of children with other defects (defect controls), and 100 mothers of children with no defects (normal controls) was carried out. All infants were born in upstate New York in 1980 and 1981. Matching was very close on maternal age for the...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Hook EB,Cross PK

    更新日期:1985-11-01 00:00:00

  • Length heteroplasmy in the first hypervariable segment of the human mtDNA control region.

    abstract::The first hypervariable segment of the human mtDNA control region contains a homopolymeric tract of cytosines between nt 16184 and 16193, interrupted at position 16189 by a thymine, according to the Cambridge reference sequence. A variant commonly found in population screening is a T-to-C transition at nt 16189, resul...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Bendall KE,Sykes BC

    更新日期:1995-08-01 00:00:00

  • An alternate method for demonstration of bisphosphoglyceromutase (DPGM) on starch gels.

    abstract::The phosphatase activity of bisphosphoglyceromutase (DPGM) was used to determine the phenotypes of the enzyme. DPGM was polymorphic in four Alaskan ethnic groups. ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Scott EM,Wright RC

    更新日期:1982-11-01 00:00:00

  • Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema.

    abstract::Cigarette smoke, containing reactive oxygen species, is the most important risk factor for chronic pulmonary emphysema (CPE). Heme oxygenase-1 (HO-1) plays a protective role as an antioxidant in the lung. A (GT)n dinucleotide repeat in the 5'-flanking region of human HO-1 gene shows length polymorphism and could modul...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302729

    authors: Yamada N,Yamaya M,Okinaga S,Nakayama K,Sekizawa K,Shibahara S,Sasaki H

    更新日期:2000-01-01 00:00:00

  • Gonadoblastoma: molecular definition of the susceptibility region on the Y chromosome.

    abstract::Using sequence-tagged sites we have performed deletion mapping of the Y chromosome in sex-reversed female patients with a Y chromosome and gonadoblastoma. The GBY gene (gonadoblastoma locus on the Y chromosome) was sublocalized to a small region near the centromere of the Y chromosome. We estimate the size of the GBY ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Tsuchiya K,Reijo R,Page DC,Disteche CM

    更新日期:1995-12-01 00:00:00

  • Evidence for the close linkage between lymphocyte cytosol polypeptide with molecular weight of 64,000 (LCP1) and esterase D.

    abstract::The genetic linkage of the loci for lymphocyte cytosol polypeptide with molecular weight of 64,000 (LCP1) and esterase (ESD) were examined by two-dimensional gel electrophoresis using blood from four informative families. No recombinants were observed in the four families totaling 17 children, giving a summed lod scor...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kondo I,Hamaguchi H

    更新日期:1985-11-01 00:00:00

  • Mitochondrial neurogastrointestinal encephalomyopathy syndrome maps to chromosome 22q13.32-qter.

    abstract::Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) syndrome is a rare, multisystem disorder characterized clinically by ptosis, progressive external ophthalmoplegia, gastrointestinal dysmotility, leukoencephalopathy, thin body habitus, and myopathy. Laboratory studies reveal defects of oxidative-phosphoryla...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/301979

    authors: Hirano M,Garcia-de-Yebenes J,Jones AC,Nishino I,DiMauro S,Carlo JR,Bender AN,Hahn AF,Salberg LM,Weeks DE,Nygaard TG

    更新日期:1998-08-01 00:00:00

  • Chronic and recurrent otitis media: a genome scan for susceptibility loci.

    abstract::Otitis media (OM) is the most common childhood disease. Almost all children experience at least one episode, but morbidity is greatest in children who experience chronic/recurrent OM (COME/ROM). There is mounting evidence that COME/ROM clusters in families and exhibits substantial heritability. Subjects who had tympan...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/426061

    authors: Daly KA,Brown WM,Segade F,Bowden DW,Keats BJ,Lindgren BR,Levine SC,Rich SS

    更新日期:2004-12-01 00:00:00

  • Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits.

    abstract::Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2017.01.027

    authors: Civelek M,Wu Y,Pan C,Raulerson CK,Ko A,He A,Tilford C,Saleem NK,Stančáková A,Scott LJ,Fuchsberger C,Stringham HM,Jackson AU,Narisu N,Chines PS,Small KS,Kuusisto J,Parks BW,Pajukanta P,Kirchgessner T,Collins FS,G

    更新日期:2017-03-02 00:00:00

  • Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation.

    abstract::Activating mutations in the genes for fibroblast growth factor receptors 1-3 (FGFR1-3) are responsible for a diverse group of skeletal disorders. In general, mutations in FGFR1 and FGFR2 cause the majority of syndromes involving craniosynostosis, whereas the dwarfing syndromes are largely associated with FGFR3 mutatio...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/427956

    authors: White KE,Cabral JM,Davis SI,Fishburn T,Evans WE,Ichikawa S,Fields J,Yu X,Shaw NJ,McLellan NJ,McKeown C,Fitzpatrick D,Yu K,Ornitz DM,Econs MJ

    更新日期:2005-02-01 00:00:00

  • RP2 and RPGR mutations and clinical correlations in patients with X-linked retinitis pigmentosa.

    abstract::We determined the mutation spectrum of the RP2 and RPGR genes in patients with X-linked retinitis pigmentosa (XLRP) and searched for correlations between categories of mutation and severity of disease. We screened 187 unrelated male patients for mutations, including 135 with a prior clinical diagnosis of XLRP, 11 with...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/379379

    authors: Sharon D,Sandberg MA,Rabe VW,Stillberger M,Dryja TP,Berson EL

    更新日期:2003-11-01 00:00:00

  • Gyrate atrophy of the choroid and retina: characterization of mutant ornithine aminotransferase and mechanism of response to vitamin B6.

    abstract::The purpose of this study was to characterize the mutant enzyme in nine patients with gyrate atrophy of the choroid and retina associated with ornithine aminotransferase (OAT) deficiency, to elucidate the mechanism of response to pyridoxine in four pyridoxine-responsive patients, and to determine the extent of genetic...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Kennaway NG,Stankova L,Wirtz MK,Weleber RG

    更新日期:1989-03-01 00:00:00

  • New approach for isolation of VNTR markers.

    abstract::Elsewhere we have reported an efficient method for isolating VNTR (Variable Number of Tandem Repeats) markers. Several of the VNTR markers isolated in those experiments were sequenced, and a DNA sequence of 9 bp (GNNGTGGG) emerged as an apparent consensus sequence for VNTR markers. To confirm this result and to develo...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Nakamura Y,Carlson M,Krapcho K,Kanamori M,White R

    更新日期:1988-12-01 00:00:00

  • Mutations in the SPARC-related modular calcium-binding protein 1 gene, SMOC1, cause waardenburg anophthalmia syndrome.

    abstract::Waardenburg anophthalmia syndrome, also known as microphthalmia with limb anomalies, ophthalmoacromelic syndrome, and anophthalmia-syndactyly, is a rare autosomal-recessive developmental disorder that has been mapped to 10p11.23. Here we show that this disease is heterogeneous by reporting on a consanguineous family, ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2010.12.002

    authors: Abouzeid H,Boisset G,Favez T,Youssef M,Marzouk I,Shakankiry N,Bayoumi N,Descombes P,Agosti C,Munier FL,Schorderet DF

    更新日期:2011-01-07 00:00:00

  • Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy.

    abstract::Distal hereditary motor neuropathies comprise a clinically and genetically heterogeneous group of disorders. We recently mapped an X-linked form of this condition to chromosome Xq13.1-q21 in two large unrelated families. The region of genetic linkage included ATP7A, which encodes a copper-transporting P-type ATPase mu...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2010.01.027

    authors: Kennerson ML,Nicholson GA,Kaler SG,Kowalski B,Mercer JF,Tang J,Llanos RM,Chu S,Takata RI,Speck-Martins CE,Baets J,Almeida-Souza L,Fischer D,Timmerman V,Taylor PE,Scherer SS,Ferguson TA,Bird TD,De Jonghe P,Feely SM,

    更新日期:2010-03-12 00:00:00

  • The mutational spectrum in Treacher Collins syndrome reveals a predominance of mutations that create a premature-termination codon.

    abstract::Treacher Collins syndrome (TCS) is an autosomal dominant disorder of craniofacial development, the features of which include conductive hearing loss and cleft palate. The TCS locus has been mapped to human chromosome 5q31.3-32 and the mutated gene identified. In the current investigation, 25 previously undescribed mut...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Edwards SJ,Gladwin AJ,Dixon MJ

    更新日期:1997-03-01 00:00:00

  • A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population.

    abstract::Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/518720

    authors: Liu F,Arias-Vásquez A,Sleegers K,Aulchenko YS,Kayser M,Sanchez-Juan P,Feng BJ,Bertoli-Avella AM,van Swieten J,Axenovich TI,Heutink P,van Broeckhoven C,Oostra BA,van Duijn CM

    更新日期:2007-07-01 00:00:00

  • PubCaseFinder: A Case-Report-Based, Phenotype-Driven Differential-Diagnosis System for Rare Diseases.

    abstract::Recently, to speed up the differential-diagnosis process based on symptoms and signs observed from an affected individual in the diagnosis of rare diseases, researchers have developed and implemented phenotype-driven differential-diagnosis systems. The performance of those systems relies on the quantity and quality of...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2018.08.003

    authors: Fujiwara T,Yamamoto Y,Kim JD,Buske O,Takagi T

    更新日期:2018-09-06 00:00:00

  • Hereditary mucoepithelial dysplasia: a disease apparently of desmosome and gap junction formation.

    abstract::A previously unrecognized autosomal dominant syndrome affecting oral, nasal, vaginal, urethral, anal, bladder, and conjunctival mucosa with cataracts, follicular keratosis, nonscarring alopecia, and terminal lung disease is described in a four-generation kindred of German extraction. Severe photophobia, tearing, and n...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Witkop CJ Jr,White JG,King RA,Dahl MV,Young WG,Sauk JJ Jr

    更新日期:1979-07-01 00:00:00

  • Evidence that methylation of the FMR-I locus is responsible for variable phenotypic expression of the fragile X syndrome.

    abstract::DNA at the FMR-1 locus was analyzed by Southern blot using probe StB12.3 in an unusual fragile X family with six brothers, three of whom are affected with fragile X to varying degrees, two of whom are nonpenetrant carriers, and one of whom is unaffected. Fragile X chromosome studies, detailed physical examinations, an...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: McConkie-Rosell A,Lachiewicz AM,Spiridigliozzi GA,Tarleton J,Schoenwald S,Phelan MC,Goonewardena P,Ding X,Brown WT

    更新日期:1993-10-01 00:00:00

  • Human RAD50 deficiency in a Nijmegen breakage syndrome-like disorder.

    abstract::The MRE11/RAD50/NBN (MRN) complex plays a key role in recognizing and signaling DNA double-strand breaks (DSBs). Hypomorphic mutations in NBN (previously known as NBS1) and MRE11A give rise to the autosomal-recessive diseases Nijmegen breakage syndrome (NBS) and ataxia-telangiectasia-like disorder (ATLD), respectively...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2009.04.010

    authors: Waltes R,Kalb R,Gatei M,Kijas AW,Stumm M,Sobeck A,Wieland B,Varon R,Lerenthal Y,Lavin MF,Schindler D,Dörk T

    更新日期:2009-05-01 00:00:00

  • A major locus for myoclonus-dystonia maps to chromosome 7q in eight families.

    abstract::Myoclonus-dystonia (M-D) is an autosomal dominant disorder characterized by myoclonic and dystonic muscle contractions that are often responsive to alcohol. The dopamine D2 receptor gene (DRD2) on chromosome 11q has been implicated in one family with this syndrome, and linkage to a 28-cM region on 7q has been reported...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Klein C,Schilling K,Saunders-Pullman RJ,Garrels J,Breakefield XO,Brin MF,deLeon D,Doheny D,Fahn S,Fink JS,Forsgren L,Friedman J,Frucht S,Harris J,Holmgren G,Kis B,Kurlan R,Kyllerman M,Lang AE,Leung J,Raymond D,R

    更新日期:2000-11-01 00:00:00

  • Linkage of an autosomal dominant clefting syndrome (Van der Woude) to loci on chromosome Iq.

    abstract::Van der Woude syndrome (VWS) is an autosomal dominant disorder in which affected individuals have one or more of the following manifestations: cleft lip, cleft palate, hypodontia, or paramedian lower-lip pits. VWS is a well-characterized example of a single-gene abnormality that disturbs normal craniofacial morphogene...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:

    authors: Murray JC,Nishimura DY,Buetow KH,Ardinger HH,Spence MA,Sparkes RS,Falk RE,Falk PM,Gardner RJ,Harkness EM

    更新日期:1990-03-01 00:00:00

  • A critical appraisal of the scientific basis of commercial genomic profiles used to assess health risks and personalize health interventions.

    abstract::Predictive genomic profiling used to produce personalized nutrition and other lifestyle health recommendations is currently offered directly to consumers. By examining previous meta-analyses and HuGE reviews, we assessed the scientific evidence supporting the purported gene-disease associations for genes included in g...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2007.12.020

    authors: Janssens AC,Gwinn M,Bradley LA,Oostra BA,van Duijn CM,Khoury MJ

    更新日期:2008-03-01 00:00:00

  • Global analysis of DNA methylation variation in adipose tissue from twins reveals links to disease-associated variants in distal regulatory elements.

    abstract::Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Hum...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2013.10.004

    authors: Grundberg E,Meduri E,Sandling JK,Hedman AK,Keildson S,Buil A,Busche S,Yuan W,Nisbet J,Sekowska M,Wilk A,Barrett A,Small KS,Ge B,Caron M,Shin SY,Multiple Tissue Human Expression Resource Consortium.,Lathrop M,Dermitzak

    更新日期:2013-11-07 00:00:00

  • Mutation rates in humans. I. Overall and sex-specific rates obtained from a population study of hemophilia B.

    abstract::A population-based study of hemophilia B mutations was conducted in the United Kingdom in order to construct a national confidential database of mutations and pedigrees to be used for the provision of carrier and prenatal diagnoses based on mutation detection. This allowed the direct estimate of overall (micro), male ...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1086/302651

    authors: Green PM,Saad S,Lewis CM,Giannelli F

    更新日期:1999-12-01 00:00:00

  • Topical enzyme-replacement therapy restores transglutaminase 1 activity and corrects architecture of transglutaminase-1-deficient skin grafts.

    abstract::Transglutaminase-1 (TG1)-deficient autosomal-recessive congenital ichthyosis (ARCI) is a rare and severe genetic skin disease caused by mutations in TGM1. It is characterized by collodion babies at birth, dramatically increased transepidermal water loss (TEWL), and lifelong pronounced scaling. The disease has a tremen...

    journal_title:American journal of human genetics

    pub_type: 杂志文章

    doi:10.1016/j.ajhg.2013.08.003

    authors: Aufenvenne K,Larcher F,Hausser I,Duarte B,Oji V,Nikolenko H,Del Rio M,Dathe M,Traupe H

    更新日期:2013-10-03 00:00:00